1. Field of the Invention
The present invention concerns the use of clomiphene to increase bone mass, i.e., to treat and/or prevent osteoporosis, in humans.
Background Information
Osteoporosis is a condition wherein the patient suffers from decreased bone mass, involving loss of both mineral and protein matrix components. Osteoporosis curs in patients suffering from estrogen deficit (postmenopausal), catabolic hormone excess (e.g., Cushing's disease), long-term administration of corticosteroids in large doses, immobilization, liver disease, gonadal dysgenesis and osteogenesis imperfecta. The chief complications of osteoporosis are bone pain, fracture, kyphosis and invalidism. More common in females than in males and in Caucasians than in Negroes, osteoporosis is rarer in premenopausal women.
In most cases, especially in the postmenopausal form, symptoms begin with pain in the weight-bearing vertebrae, i.e., T-8 and below. It is usually localized in the vertebrae, does not radiate and is not associated with generalized bone tenderness. Local tenderness is present if fracture occurs. Loss of height may result from multiple vertebral fractures and kyphosis and can be confirmed by disparity between the height and span in the absence of other causes for such disparity (e.g., arachnodactyly or eunuchoidism). Serum calcium and alkaline phosphatase levels are normal; serum phosphorus may be slightly elevated in postmenopausal women and in hyperthyroid patients, but low in Cushing's disease.
Osteoporosis is generally detected by x-ray examination. The vertebrae show loss of trabecular structure, increased contrast between the relatively preserved cortex and more seriously involved spongiosa, biconcavity, Schmorl's nodules and wedge fractures with the apex anterior. Reliance on subjective impressions of bone density if often misleading. Eburnation or thickening of the superior and inferior vertebral plates distinguishes the osteoporosis of Cushing's disease or of corticosteroid therapy from other varieties. Corticosteroid-induced osteoporosis is more likely to produce rib fractures and exuberant callus formation.
Heretofore, treatment of osteoporosis was both supportive and specific. The patient was instructed to remain as active as possible and in some instances the patient required a supporting corset. Correction of the underlying cause usually stops progression of the disease, but does not restore bone mass except in the cure of Cushing's disease in children. Treatment for the most common form of osteoporosis (i.e., in postmenopausal women) has been the subject of much controversy. Cyclic estrogen administration orally (conjugated estrogens 1.25 mg, or diethylstilbestrol 0.5 mg, or ethinyl estradiol 0.05 mg, once/day omitting 5 days each month) often relieves pain and was heretofore the only long-term therapy reported to prevent further fractures. Since x-rays show no restoration of bone mass, large doses of calcium (2 to 6 Gm/day orally), vitamin D, or fluoride have been tried. Subjective improvement and positive calcium balance have been reported. However, phosphate is not retained, indicating that bone mineral is not deposited; others report no significant calcium retention. Fluoride has been advocated on epidemiologic grounds, since bones appear more dense in areas where the water contains large amounts of fluoride. Fluorosis, however, produces brittle bones and ectopic calcification; and calcium in large doses may cause hypercalciuria and kidney stones. Moreover, unlike estrogens, neither has been shown to stop further fractures of postmenopausal osteoporosis. High doses of calcium and treatment with fluoride, therefore, must be considered investigational. Calcitonin, which inhibits bone resorption, has not been adequately evaluated. Androgen and other anabolic steroid therapy are no longer considered advisable because of undesirable virilization.
Estrogens have a profound effect on bone homeostasis, (B. L. Riggs, J. Jowsey, R. S. Goldsmith, P. J. Kelly, D. L. Hoffman and C. D. Arnaud, "Short and Long Term Effects of Estrogen and Synthetic Anabolic Hormone in Postmenopausal Osteoporosis", Clin. Invest., 51, 1659, (1972) and F. W. Lafferty, G. E. Spencer and O. H. Pearson, "Effects of Androgens, Estrogens and High Calcium Intakes on Bone Formation and Resorption in Osteoporosis, Am. J. Med., 36, 514, (1964)), although the mechanisms by which estrogens actually produce their effects on the bone have not been determined. Estrogens are well known to be potent therapeutic agents in the prevention of progressive bone mass reduction in osteoporotic women after the onset of menopause, (C. Christiansen, M. S. Christensen, P. McNair, C. Hagen, K. E. Stocklun and I. Transbol, "Prevention of Early Postmenopausal Bone Loss: Controlled 2-year Study in 315 Normal Females", Eur. J. Clin. Invest., 10, 273, (1980); C. Christiansen, R. B. Mazess, I. Transbol and G. F. Jensen, "Factors in Response to Treatment of Early Postmenopausal Bone Loss", Calcif. Tissue Int., 33, 575, (1981); S. Meema, M. L. Bunker and H. E. Meema, "Preventive Effect of Estrogen on Postmenopausal Bone Loss", Arch. Intern Med., 135, 1436, (1975); B. E. C. Nordin, A. Horsman, R. G. Grilly et al, "Treatment of Spinal Osteoporosis in Postmenopausal Women", Br. Med. J., 280, 451-454, (1980); A. Horsman, B. E. C. Nordin, J. C. Gallagher et al, "Observations of Sequential Changes in Bone Mass in Postmenopausal women: A Controlled Trial of Estrogen and Calcium Therapy", Calcif. Tissue Res., 22, (suppl) 217-224, (1977); S. Campbell and M. Whitehead, "Estrogen Therapy and the Postmenopausal Syndrome", Clin. Obstet. Gynecol. 4, 1-30, (1977); F. L. Geola, A. M. Frumar, I. V. Tataryn et al, "Biological Effects of Various Doses of Conjugated Equine Estrogens in Postmenopausal Women", Clin. Endocrinol. Metab., 51, 620-625, (1980) and B. Riis, K. Thomsen and C. Christiansen, "Does Calcium Supplementation Prevent Postmenopausal Bone Loss? A Double-blind, Controlled Study", N. Engl. J. Med., 316, 173-177, (1987)).
Clomiphene is a drug that is used to induce ovulation in infertile women. It is a competitive antagonist to estrogen. While clomiphene displays some anti-estrogenic properties, it also has estrogenic properties depending upon specie and tissue. Since clomiphene has a negative effect upon the endometrium, causing it to become atrophic, (E. Kokko, O. Janne, A. Kauppila et al, "Cyclic Clomiphene Citrate Treatment Lowers Cytosol Estrogen and Progestin Receptor Concentrations in the Endometrium of Postmenopausal Women on Estrogen Replacement Therapy", J. Clin. Endocrinol. Metab., 52, 345-349, (1981)), it was heretofore believed that clomiphene also has a negative effect on bone mass in humans.
Animal studies have shown that clomiphene prevents deterioration of the femoral bone in adult ovariectomized rats, (P. T. Beall, L. K. Misra, R. L. Young, H. J. Spjut, H. J. Evans and LeBlanc, "Clomiphene Protects Against Osteoporosis in the Mature Ovariectomized Rat", Calcif. Tissue Int., 36, 123, (1984)). Likewise, clomiphene and tamoxifen (also an estrogen agonist-antagonist) have been shown to completely block parathyroid-induced bone resorption in vitro, (P. J. Stewart and P. H. Stern, "Effects of the Antiestrogens tamoxifen and Clomiphene on Bone Resorption In Vitro", Endocrinol., 118, 125-131, (1986)). High doses of clomiphene have been reported to be effective as high-dose conjugated equine estrogens for conservation of urinary calcium in a primate model, (G. D. Hodgen, A. L. Goodman, A. O'Connor et al, "Menopause in Rhesus Monkeys: Model for Study of Disorders in the Human Climacteric", Am. J. Obstet. Gynecol., 127, 581-584, (1977)). Consequently, it appears that clomiphene in humans may also act as an estrogen at certain target cells such as bone, while acting as an anti-estrogen on other cells such as the endometrium. Importantly, unlike estrogen, clomiphene does not induce mitogenic effects on uterine endometrium, (J. A. Wall, R. R. Franklin and R. H. Kaufman, "Reversal of Benign and Malignant Endometrial Changes with Clomiphene", Am. J. Obstet. Gynecol., 88, 1072, (1964)).